Alpha-1 Antitrypsin Deficiency is an autosomal recessive disease caused by mutations in the SERPINA1 gene resulting in low levels of alpha-1 antitrypsin (AAT) protein. This puts individuals at risk for lung and liver disease. In the lungs, a lack of AAT allows proteases to destroy tissue and cause emphysema. In the liver, mutated AAT accumulates in hepatocytes and can lead to cirrhosis. The disease is diagnosed through blood tests measuring AAT levels and treated through AAT augmentation therapy or liver transplantation for end-stage liver disease.

1. ALPHA-1
ANTITRYPSIN
DEFICIENCY Jeevan kishore
Group : 16

2. Inheritance
• Alpha-1 Antitrypsin Deficiency is a single gene
inheritance (Mendelian).
• You inherited an allele from each parent.
Autosomal co-dominant
Autosomal Recessive
AA = A normal child =25% Aa = A
carrier child =50% aa = An affected
child =25%
A a
A
a
AA Aa
Aa aa

3. • Autosomal recessive disease, causing deficiency and low
serum level of
alpha-1-antitrypsin (AAT)
• Commonly presents with:
–Liver disease (neonatal hepatitis, Jaundice, cirrhosis)
–Lung disease (panacinar emphysema)
• AAT deficiency can also presents with:
– Cutaneous necrotizing panniculits
– MPGN and infantile nephrotic syndrome

4. • Alpha-1-antitrypsin is an acute-phase plasma glycoprotein
– Serum level is elevated during infections and other inflammatory
conditions
• AAT is functioning as a protease inhibitor (Pi), which inhibits
proteases
released at sites of inflammation
– Mainly neutrophil elastase, cathepsin G, and proteinase 3
• It is synthesized mainly by liver cells
• It is encoded by SERPINA1 gene on chromosome 14
– (Serine Protease INhibitor A1)
– Previously known as Pi gene

5. • About 75 allelic variants are identified and ordered alphabetically
according to their products’ migration pattern during electrophoresis
• Most of these variants are normal, the most common “normal” one is
PiMM (90% of individuals)
• The most common “deficiency” variant is PiZZ
• Due to amino acid substitution (lysine for glutamic acid at position 342)
• Low serum AAT level
• Heterozygous PiMZ shows milder disease than homozygous PiZZ
– This is called “autosomal codominant expression”
• Other less common “deficiency” variants
• Pi-null: No detectable serum AAT – Very aggressive disease
• Pi-S: moderate decrease in serum AAT – No clinical disease

6. PATHOGENESIS
• Due to missense mutation (amino acid substitution), causing abnormal
protein folding and resulting in:
– Blockage of protein transfer from the endoplasmic reticulum to Golgi apparatus
– Prevention of protein secretion into the circulation
• Accumulation of misfolded AAT in hepatocytes results in formation of cytoplasmic
inclusions and apoptosis
• Absent/low circulatory AAT results in unopposed leukocyte proteases activity during any
inflammatory process
– In lungs, destruction of connective tissues causes emphysema
• This can be aggravated by smoking (by increases the activation and influx of
neutrophils)

7. GROSS
•Lung:
•Panacinar emphysema
(enlarged cystic lung)
•Liver:
•Non-specific
•Advanced disease cirrhosis

8. MICROSCOPY
• Lung
• Characteristic feature:
• Abnormal enlargement
of airspaces
• The whole acinus is
involved (i.e. panacinar)
• Other features:
• Variable inflammation
• No or little fibrosis

9. • Liver
• Characteristic feature
• Round to oval intracytoplasmic
eosinophilic inclusions
• Mainly seen in Periportal “zone 1”
hepatocytes
• NOT seen in infants < 3 months
• Other features:
• Neonatal giant cell hepatitis
• Variable cholestasis, inflammation,
ductular reaction
• Rare Mallory bodies and fatty change
• Advanced cases:
• Portal fibrosis and Cirrhosis – HCC

10. • Neonatal giant cell hepatitis
• An injury pattern seen in neonates
• Associated with wide variety of liver diseases
• The most frequently associated disorder is
alpha-1 antitrypsin deficiency
• The hallmark is syncytial giant cell
transformation of hepatocytes
• Thought to reflect hepatocyte cell fusion
and/or mitotic inhibition
• Ductular reaction is usually mild in AAT
deficiency, but:
• in some case it may predominate
(simulate biliary atresia)
• In other cases, there may be paucity of
intrahepatic bile ducts

11. Clinical Presentation
• In this disease the α-1 AT cannot go to the blood stream, so it
accumulates in the liver, and causes liver damage like jaundice,
cirrhosis, and increased risk of liver cancer.
• If α-1 AT is not going to the blood stream, it is not going to the
lungs. Now the NE is free to attack the lungs, and cause lung
diseases such as COPD, Emphysema, Chronic Bronchitis, etc..

12. Signs and Symptoms
• Jaundice
• Dyspnea
• Cough
• Wheezing
• Recurrent
pulmonary
infections
• Rapid
heartbeat
upon standing
• Tiredness
• Vision
problems
• Weight loss

13. Diagnosis
• It is difficult to diagnose this disease because when the patient
has COPD or Emphysema, you don’t think about Alpha-1
Antitrypsin deficiency.
• More than 90% of cases are not diagnosed.
• At first, many people who have AAT deficiency are diagnosed with
asthma. This is because wheezing also is a symptom of asthma.
Also, people who have AAT deficiency respond well to asthma
medicines.
• You can diagnose by taking a blood test that measures the level
of the enzyme α-1 AT.This test is simple and highly accurate.

14. • We don’t test anyone with emphysema, these are
people that you can suspect:
People who develop emphysema at younger age
<45.
Non-smokers who develop emphysema at any age.
People with unexplained liver or lung disease.
Family history of chronic lung or liver diseases.

15. SPECIAL STUDIES
• Laboratory:
• Detection of abnormal protein by
electrophoresis
• Special stains:
• Liver cytoplasmic inclusions are PAS positive
and Diastase resistant
• IHC:
• Liver cytoplasmic inclusions are AAT positive
• Electron microscopy:
• Hepatocytes shows granular material
“misfolded protein” in dilated
endoplasmic reticulum

16. DIFFERENTIAL DIAGNOSIS
L u n g
• Other types of emphysema
• Other causes of obstructive lung diseases
• Other causes of congenital / cystic lung diseases

17. DIFFERENTIAL DIAGNOSIS
Chronic
bronchitis
Bronchiectasis Asthma
Small-airway
disease
“bronchiolitis”
Emphysema
Site B r o n c h u s Bronchioles Alveoli
Major
pathology
• Mucous gland
hyperplasia
• Excess mucus
• Inflammation
• Airway
dilation &
scarring
• Smooth
muscle
hyperplasia
• Excess mucus
• Inflammation
(eosinophils)
• Inflammatory
scarring &
obliteration
• Airspace
enlargement
• Wall
destruction
• No fibrosis
Other obstructive lung diseases:

18. DIFFERENTIAL DIAGNOSIS
` • Congenital:
– Bronchogenic cysts
– Congenital pulmonary cysts
– Congenital pulmonary airway malformation
– Congenital lobar emphysema
– Pulmonary sequestration
• Acquired:
– Healed abscess
– Honeycombing
• Mixed:
– Cystic fibrosis
No destruction of alveoli
Fibrosis

19. DIFFERENTIAL DIAGNOSIS
L i v e r
• Other causes of giant cell transformation
• Other causes of neonatal cholestasis
• Other causes of cirrhosis
α1-Antitrypsin deficiency is one of the few liver
diseases that can still be diagnosed in an end-
stage liver explant because of the PAS-positive and
diastase-resistant globules that remain in the
hepatocyte cytoplasm

20. Treatment
• Lung:
– "Augmentation therapy“
• infusion of purified AAT from pooled human plasma
– Avoid cigarette smoking
• Liver:
– Mainly symptomatic and supportive
– Liver transplantation in end-stagedisease